Many useful ophthalmic compounds are solids. Those solids which are soluble in ophthalmic carriers or vehicles present little or no difficulty when preparing a composition for ophthalmic use. However, those solids which are insoluble in ophthalmic carriers must be formulated as compositions such as suspensions or emulsion in order to obtain a proper delivery system. Moreover, forms of useful ophthalmic compounds which are insoluble in ophthalmic carriers are often found desirable in order to prolong the particular therapeutic action of the compound.
A pharmaceutically acceptable ophthalmic composition possesses certain essential characteristics, among which are: (1) the dispersed or suspended material should not settle too rapidly from the carrier to be available in the required concentration in the carrier for effective administration to the eye of the patient; (2) the particles of dispersed or suspended material which do finally settle to the bottom of the vessel holding the composition must not form an intractable hard cake but should be readily re-dispersed into a uniform composition when the vessel is shaken; (3) the particles size of the dispersed materials should be fine enough to avoid any irritation to the eye.
Major problems related to ophthalmic compositions are crystallization and agglomeration of active ingredients during preparation as well as during storage. Crystallization or agglomeration of active leads to non-uniformity of dose, difficulty of administration, irritation to eye due to large drug particles and/or any ocular adverse effect due to high drug concentration or failure of treatment due to low drug concentration.
In most cases crystallization of active ingredients useful for ophthalmic use like carbonic anhydrase inhibitor, beta-blockers or others actives, occurs during preparation. Sterilization by autoclaving leads to increase in solubility of the actives in the preparation and large crystals are formed during cool down phase. Aseptic ball milling of this final composition is not always practical. Aseptic addition of the all actives to a sterile vehicle is also not practical as the all actives cannot be sterilized by conventional means due to stability problem. Dry heat sterilization causes melting of the material. Sterilization by ethylene oxide introduces unacceptable degradation products and residues, and sterilization by gamma irradiation of micronized material produces degradation products unacceptable for regulatory filing. Another reason for crystallization is change in pH due to addition of salts, acids or bases.
During storage, the composition is left standing for a long time, hence secondary particles are formed due to partial agglomeration caused by mutual adhesion of suspended particles, or a hard deposit layer (caking) on the bottom surface of a container; or may have a lowered pH. Such formation of secondary particles or caking causes problems in terms of particle size and re-dispersibility (hereinafter secondary particles and caking are sometimes integrally referred to as agglomerates). It has been found that the caking is common problem due to unequal particle size distribution. The fine particles take the void space in-between the large particles and form strong caking.
In one preferred embodiment, the pharmaceutical ophthalmic compositions comprise pharmaceutically active carbonic anhydrase inhibitors (CAIs) such as R 4-ethylamino-3,4-dihydro-2-(3-methoxy)propyl-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1 dioxide, which is known as brinzolamide. This compound is disclosed in U.S. Pat. No. 5,378,703 (Dean, et al.).
U.S. Pat. No. 6,071,904 discloses processes for preparation of brinzolamide ophthalmic composition.
We have now developed simpler and cost effective process(s) to prepare pharmaceutical ophthalmic compositions.